Pharmacogenetics of aspirin resistance: a comprehensive systematic review

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • A genetic basis for aspirin resistance has been postulated to exist. • The individual studies published have been too small to allow reliable conclusions to be drawn. • In order to clarify what, if any, genetic basis exists for aspirin resistance, we have undertaken, to our knowledge, the largest and most comprehensive systematic review conducted to‐date in this field. WHAT THIS STUDY ADDS • There is a significant association between the PlA1/A2 molecular variant and aspirin resistance in healthy subjects, with the effect diminishing in the presence of cardiovascular disease. • However further studies are needed to confirm this. • We argue that investigators now need to agree on a standard technique to measure and define aspirin resistance. AIMS The aim was to perform a systematic review of all candidate gene association studies in aspirin resistance. METHODS Electronic databases were searched up until 1 December 2007 for all studies investigating any candidate gene for aspirin resistance in humans. Aspirin resistance was required to have been measured by a standardized laboratory technique to be included in the analysis. RESULTS Within 31 studies, 50 polymorphisms in 11 genes were investigated in 2834 subjects. The PlA1/A2 polymorphism in the GPIIIa platelet receptor was the most frequently investigated, with 19 studies in 1389 subjects. The PlA1/A2 variant was significantly associated with aspirin resistance when measured in healthy subjects [odds ratio (OR) 2.36, 95% confidence interval (CI) 1.24, 4.49; P = 0.009]. Combining genetic data from all studies (comprising both healthy subjects and those with cardiovascular disease) reduced the observed effect size (OR 1.14, 95% CI 0.84, 1.54; P = 0.40). Moreover, the observed effect of PlA1/A2 genotype varied depending on the methodology used for determining aspirin sensitivity/resistance. No significant association was found with aspirin resistance in four other investigated polymorphisms in the COX‐1, GPla, P2Y1 or P2Y12 genes. CONCLUSIONS Our data support a genetic association between the PlA1/A2 molecular variant and aspirin resistance in healthy subjects, with the effect diminishing in the presence of cardiovascular disease. The laboratory methodology used influences the detection of aspirin resistance. However, as heterogeneity was significant and our results are based on a limited number of studies, further studies are required to confirm our findings.

Aspirin Resistance: Current Status and Role of Tailored Therapy

“…Although the response to aspirin appears to be heritable in certain families with strong family history of coronary heart disease, 27 studies investigating genetic polymorphism as an explanation for aspirin resistance have so far been conflicting. 28 Interestingly, among high-risk black and white families with strong family history of heart disease, aspirin response via COX-1-independent pathways appears to be more heritable than response by COX-1-dependent pathways. 27 Platelet turnover is another mechanism postulated to contribute to aspirin resistance.…”

Platelet Response to Aspirin in Chinese Stroke Patients is Independent of Genetic Polymorphisms of COX-1 C50T and COX-2 G765C

“…In addition, numerous studies have investigated the role of genetic factors that contribute to the resistance or augmented response to aspirin 14,15) ; however, they have conflicting results. A systematic review revealed that the PlA1/A2 variant is significantly associated with AR, but no significant association was found with AR in polymorphisms of COX-1, GPla, P2Y1, or P2Y12 genes 16) . Aspirin leads to COX-1 inactivation and decreased TXA2 production, achieving the goal of antithrombotic therapy 17) .…”

Aspirin resistance: Where are we now?

“…COX -1 enzyme gene, P2Y1 and P2Y12 platelet receptor genes and glycoprotein (GP) IIb/IIIa genes are most studied genes in aspirin resistance, but there are conflicting results regarding association of aspirin non-response and gene polymorphism (19)(20)(21). A meta-analysis of 31 studies examining 50 polymorphisms in 11 genes showed that only GPIIIa gene polymorphism was associated with aspirin resistance (22).…”